How can we make the best use of Vitamin D for anti-ageing benefits?
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Subash ChapagainSep 24, 2020
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What is the best way of for Vitamin-D utilization for longevity?
Previously thought to be cardinal only in calcium homeostasis, Vitamin D has been discovered to have multiple implications in human health and longevity. As Vitamin D receptors have been found in the nervous, cardiovascular and endocrine systems, it has been evident that its deficiency can result in many diseases. At older ages, Vitamin D levels drop down as a result if reduced cutaneous synthesis and dietary intake of vitamin D. Moreover, low levels of vitamin D have been linked to ageing-associated diseases like osteoporosis, hypertension, type 2 diabetes, cancer, cardiovascular disease, cognitive decline and depression .
Diet, supplements and sunlight are the key sources of Vitamin D. It is naturally present in fish cod liver oil (Vitamin D3), UV exposed mushrooms (Vitamin D2) and is also fortified in food products such as orange juice and milk, and available as supplements (D2 and D3). Upon exposure to solar UV radiation, 7-dehydrocholesterol in the skin is converted to form pre-vitamin D3 and later to vitamin D3. The ingested Vitamin D2 and D3 circulate to the liver, undergo hydroxylation to 25 hydroxyvitamin D and then to the kidney where it goes the second hydroxylation to 1,25 dihydroxy vitamin D, the biologically active form of vitamin D commonly known as Calcitriol. The rise in the concentration of Calcitriol causes the vitamin D nuclear receptors (VDRs) throughout the body to stimulate, starting the activation of transcription of a number of genes that are potentially involved in crucial biological actions that determine ageing and longevity .
Molecular links to anti-ageing activities of Vitamin D has been established from an experimental study that used C. elegans as a model organism. The study has corroborated the earlier observations that short-term treatment of mouse models of Alzheimer’s Disease with vitamin D reduces amyloid-β (Aβ) peptides aggregation, increasing cognition . Mark et. al. have shown that Vitamin D helps maintain protein homeostasis and slows ageing as much as 33% in C. elegans via stress response IRE-1, XBP-1 and SKN-1 gene pathways. Their results demonstrated that dietary supplementation with Vitamin D3 results in endogeneous Calcitriol production at a physiologically significant range with profound effects in lifespan. It was seen that vitamin D3 treatment slowed proteome-wide, age-related protein insolubility that is peculiar analogous observation in neurodegenerative disorders related to ageing. Since there is a decline in vitamin D production with age in humans, this observation becomes even more applicable as a therapeutic intervention .
The major source of vitamin D is exposure to sunlight with the efficiency of the conversion of precursors to vitamin D3. However, vitamin D efficacy and functioning are dependent on season, latitude, skin pigmentation, pollution, age and similar factors . However, the optimal dose of Vitamin D is still under question. Moreover, the form of Vitamin D that can best be utilized by the body is also not determined.
So, what can be the best way to make the full use of this crucial biomolecule? How can we determine the perfect amount and form for its therapeutic potential? Should it be fortified in the foods or should it be supplemented pharmacologically? What other aspects should we focus in regard to Vitamin-D utilization?
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Mark KA, Dumas KJ, Bhaumik D, et al. Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1. Cell Rep. 2016;17(5):1227-1237. doi:10.1016/j.celrep.2016.09.086
As you’ve already mentioned, vitamin D has shown some geroprotective effects in studies. Vitamin D₃ may have an impact on our epigenetic age too. In one study, the usage of a vitamin D₃ supplement (4,000 IU per day) was linked to a reduction in epigenetic age by 1.85 years (Horvath’s clock) in obese individuals.  In another study, researchers showed that a vitamin D deficiency promotes brain imbalance and results in a pro-inflammatory shift.  Therefore, vitamin D supplementation could offer neuroprotective effects and even geroprotective effects.
In the study you mentioned about C. elegans, vitamin D₃ was able to increase the lifespan of C. elegans in a dose-dependent manner. The concentrations of vitamin D₃ used were in the region of 25 to 250 μM. Apparently, 250 μM did not have any toxic effects on c. elegans. Those concentrations were well tolerated in C. elegans, as well as, having a geroprotective effect.  However, this may be a different case when it comes to humans. We should test various vitamin D₃ concentrations to observe if there are any effects on the human lifespan.
Adults are usually recommended to take 10 μg – 20 μg vitamin D₃ a day (but this does vary for different countries and their personal needs). Toxic effects have been reported when serum 25-hydroxyvitamin D levels were more than 375 nmol/L, but this does vary depending on several factors. Having too much vitamin D can result in hypercalcemia (a calcium build-up). Hypercalcemia is associated with nausea, fatigue, and needing to pee often. There are more severe complications that can arise due to hypercalcemia, including bone mineralization issues and toxicity of the heart and kidneys.  The best way to administer vitamin D₃ would be to administer a small dose every day instead of one large dose per month for prolonged periods. Taking one large dose a month for a long period can promote toxicity. 
One group of researchers conducted a seven-year study in hospital patients using 5,000 to 50,000 IU (125 μg – 1250 μg) vitamin D₃. The researchers said that the patients using these concentrations experienced no toxicity whatsoever and so these dosages seemed to be safe.  More research needs to be done regarding the optimal vitamin D₃ dosages.
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2.Kasatkina, Ludmila A., et al. "Vitamin D deficiency induces the excitation/inhibition brain imbalance and the proinflammatory shift." The International Journal of Biochemistry & Cell Biology 119 (2020): 105665.
3.Mark KA, Dumas KJ, Bhaumik D, et al. Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1. Cell Rep. 2016;17(5):1227-1237. doi:10.1016/j.celrep.2016.09.086
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